Dendritogenesis is a morphological change in cells that takes place especially in the nervous system and in the immune system. In the immune system, dendritogenesis leads to the generation of dendritic cells from monocytes. These physiologically important phenomena are not very well understood at the present time, but they are associated with an increase in the secretory activity of the cells (Martinez-Arca S. et al., 2001, J. Neurosci, 21 (11), 3830-38 and Denzer K et al., 2000, J. Cell. Sci., 113 Pt 19, 3365-74). These phenomena are induced by growth factors and cytokines. The differentiation of monocytes into dendritic cells (CD) is induced by cotreating monocytes with interleukin-4 (IL4/GM-CSF), the activation of the CDs also requiring a treatment with TNF-α (tumor necrosis factor alpha).
It is known that tumoral cells are antigenic and express at their surface antigens that are specifically recognized by lymphocytes. These antigens are peptides charged on the class I CMH molecules: a specific CD8− T lymphocyte recognizes this CMH-peptide complex. It has been shown that CDs modified ex vivo to exhibit tumoral antigens induced a specific immunity preventing and/or eradicating tumors established in mice. (Schuler P. Steinman R M, J. Exp. Med. 1997, 8, 1183-7 and Angevin, André, Zitvogel, Bull Cancer, 2000, 87(1), 107-15). It has thus been considered that CDs are potent adjuvants for inducing a therapeutic immune response.
At the present time, cellular therapy thus concerns methods for the ex vivo generation of human CDs for clinical use.
In the case especially of breast cancer, it has already been proposed to remove monocytes from the patient and to culture them in the presence of a combination of cytokines and of the antigen to be presented; the dendritic cells obtained by dendritogenesis were reinjected into the patients to develop the cytotoxic T lymphocytes specific for the antigen (Lawrence Fong and Edgar G. Engleman, Annu. Rev. Immunol., 2000, 18, 245-273).
The prior art that has just been described demonstrates the drawbacks inherent in these methods. Specifically, sensitization of the dendritic cells uses peptides derived from tumoral antigens; however, for the majority of tumors, the specific antigens have not been identified. Furthermore, to sensitize the dendritic cells, use is generally made of peptides identified in the tumoral cells by means of cytotoxic T lymphocyte clones specific for the tumor; however, the epitopes presented by the tumoral cells and those presented by the antigen-exhibiting dendritic cells are probably not the same. What is more, when dendritic cells that have been subjected to the various ex-vivo treatments described above are used, phenotypic changes may take place leading to heterogeneous cell populations that are unsuitable for therapeutic use. It is thus highly desirable to improve the methods for obtaining sensitized dendritic cells, in order to enable the development of immunotherapy.
The invention is based on the fact that it has been found that, entirely surprisingly, the differentiation of monocytes into dendritic cells can be induced in vivo by means of a class of novel sterol-based compounds. Hitherto, the use of non-peptide compounds was envisioned only for potentiating neuritogenesis (Pradines and coworkers, 1995, J. Neurochem., 64, 1954-64); there was nothing to suggest to a person skilled in the art that non-peptide molecules were capable of inducing the differentiation of monocytes into dendritic cells. According to the invention, and entirely surprisingly, it has been found that one category of sterols mimics, at low dose, the dendritogenic growth factor effect and the cytokine effect.